Medicines for the prevention and treatment of neurodegenerative diseases

ABSTRACT

Medicines for the prevention and treatment of neurodegenerative diseases such as Alzheimer&#39;s disease and schizophrenia of mammals (including human beings) through the retardation or inhibition of neurodegeneration due to hypofunction of glutamic acid receptor and which contain as an active ingredient 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives of the formula (I):  
                 
 
     wherein Het is oxadiazolyl; R 1  is hydrogen, lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, etc.; and R 2  is hydrogen, lower alkyl, cyclo-lower alkyl, substituted or unsubstituted aryl, etc., or physiologically acceptable acid addition salts thereof.

TECHNICAL FIELD

[0001] The present invention relates to a medicine for the preventionand treatment of neurodegenerative diseases comprising a5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative or aphysiologically acceptable acid addition salt thereof as an activeingredient, and use of said compound for the manufacture of a medicinefor the prevention and treatment of neurodegenerative diseases.

BACKGROUND ART

[0002] With developing into an aging society, the number of patientssuffering from neurodegenerative diseases such as Alzheimer's disease isincreasing. Alzheimer's disease is a progressive neurodegenerativedisorder of the central nervous system which symptoms are mainlyattenuation and decline of memory, and it is suggested by theneurochemical studies that the main cause is dysfunction ofneurotransmissions in plural neurotransmitter systems such asacetylcholine, γ-aminobutyric acid (GABA), glutamic acid, and dopamine.On the basis of the finding that the neuronal dysfunction occursremarkably in cholinergic system among those systems, a medicine hasbeen developed for the purpose of improvement in cognitive deficits bymeans of the activation of cholinergic system.

[0003] Besides, there are also some attempts to develop benzodiazepine(BZP) receptor inverse agonists as the therapeutic agent for treatmentof dementia. Heretofore, many studies have been done on the relationshipbetween the binding-manner to the BZP receptor and the pharmacologicalactivity, and in view of the pharmacological activity thereof, BZPagonists have been used as antianxiety drugs (e.g. diazepam), ashypnotics (e.g. triazolam), or as antiepileptic drugs (e.g. clonazepam).However, it is well-known that administration of BZP agonists causesamnesia (amnesic action) as a side effect. On the other hand, since itis known that BZP inverse agonists exhibit the actions opposite to thoseof BZP agonists, and enhance cholinergic activity which is considerablyrelated with cognitive function, the inverse agonist is expected to havethe anti-dysmnesia action (anti-amnesia action) and to activate cerebralfunction.

[0004] As an example of such a compound, WO 99/03857 discloses5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives ofthe following formula:

[0005] wherein Het is an oxadiazolyl group;

[0006] R¹ is a hydrogen, a lower alkyl group, a cyclo-lower alkyl group,a lower alkenyl group, a lower alkoxy group, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, etc.; and

[0007] R² is a hydrogen, a lower alkyl group, a cyclo-lower alkyl group,a substituted or unsubstituted aryl group, etc.,

[0008] in which it is described that said compounds exhibit selectiveand high affinity to benzodiazepine receptor and are useful asbenzodiazepine receptor ligands, especially as inverse agonists, whichare expected to be cerebral activators or therapeutic agents fortreatment of senile dementia and Alzheimer's disease.

[0009] Recently, it has been indicated that schizophrenia andAlzheimer's disease are related with the hypofunction of ion-channeltype N-methyl-D-aspartic acid (hereinafter, abbreviated to “NMDA”)receptor, which is a subtype of glutamic acid receptors. Phencyclidine,a noncompetitive antagonist of NMDA receptor, exhibits excellentpharmacological activities such as anesthetic activity andneuroprotective activity for acute encephalopathy, while it has beenever used for the undesirable purpose of extensive drug abuse as streetdrug. After E. D. Luby et al. reported that phencyclidine causedschizophrenia-like hallucination and mental aberration in human beings[Archives Neurology and Psychiatry. Vol 81, pp 363-369 (1959)], a lot ofstudies thereof have been accumulated until today. It has been provedthat phencyclidine causes schizophrenia-like hallucination and mentalaberration in human beings more strongly than amphetamine or LSD(9,10-didehydro-N,N-diethyl-6-methyl-ergoline-8β-carboxamide).Additionally, in the case of animals, it is known that NMDA receptorantagonists such as phencyclidine, MK-801 (dizocilpine maleate:(+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-iminemaleate) and ketamine, cause the enhancement of spontaneous motoractivity and aberrant behaviors related with the symptoms of mentalaberration such as hallucination, as well as ataxia, and such behavioralchanges are suppressed by medicines for schizophrenia (e.g. haloperidol,risperidone and olanzapine), antianxiety drugs (e.g. diazepam), andantagonists of NMDA receptor glycine site (e.g. HA-966:R(+)-3-amino-1-hydroxy-2-pyrrolidinone). It is also known that NMDAreceptor antagonists (MK-801, phencyclidine and ketamine) causelearning/memory disorder in animals. Consequently, a medicinesuppressing hypofunction of NMDA receptor is expected to be useful fortherapy of dysmnesia and schizophrenia.

[0010] It is known that MK-801 is a noncompetitive antagonist for NMDAreceptor, which is a subtype of glutamate receptors, and encephalicneuronopathy (leading to cell death via cell vacuolization) is caused bythe systemic administration of said agent to animals. That is, in thecase of the single application of MK-801 at moderate doses (0.3-1.0mg/kg), neuronal vacuolization is observed in the posterior cingulate(PC)/retrosplenial cortex (RS) (hereinafter, abbreviated to PC/RScortex) in 4-5 hours after administration, and in the case of higherdoses (3-10 mg/kg), necrosis of neurons and hyperplasia of glial cellsare observed in a few days to a few weeks after administration. Besides,in the case of repeated application, the damage spreads to hippocampalventral dentate gyrus and limbic regions such as entorhinal cortex andamygdala. It is presumed that the hypofunction of NMDA receptor maycause neurodegeneration in the PC/RS cortex through complicatedpolysynaptic network mechanism [in which at least 7 receptors, i.e.glutamic acid (NMDA and non-NMDA), acetylcholine-M3, adrenaline-α2,GABA-A, sigma and serotonin 2A, are involved], since suchneurodegeneration would be caused by both noncompetitive antagonists ofNMDA receptor (phencyclidine and ketamine) and competitive antagonists[e.g. D-2-amino-5-phosphono-pentanoic acid (D-AP5)]. It is consideredthat the dysfunction of NMDA receptor caused by administration of MK-801may be closely related to the onset of neurodegenerative diseases, andhence the neuronopathy induced by MK-801 will be usable as apathological model of neurodegenerative diseases [see, G. Ellison. BrainResearch Reviews. Vol 20, pp 250-267 (1995); D. F. Wozniak et al., BrainResearch. Vol 707, pp 165-179 (1996); J. W. Olney et al., J. PsychiatricResearch. Vol 33, pp 523-533 (1999); P. Andine et al., J. Pharmacol.Exp. Ther., Vol 290, pp 1393-1408 (1999)].

[0011] It is known that medicines inhibiting MK-801-induced neuronopathyinclude anticholinergic drugs (e.g. scopolamine and atropine),barbiturate hypnotics (e.g. pentobarbital and thiopental), andbenzodiazepine derivatives (e.g. diazepam) [see, J. W. Olney et al.,Science, Vol 254, pp 1515-1518 (1991)].

[0012] The present inventors have found that5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivatives ofthe formula (I) or physiologically acceptable acid addition saltsthereof exhibit an extremely potent inhibitory effect on theMK-801-induced neurodegeneration in the PC/RS cortex by using the abovepathological model.

DISCLOSURE OF INVENTION

[0013] An object of the present invention is to provide a medicine forthe prevention and treatment of neurodegenerative diseases comprising a5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of thefollowing formula (I):

[0014] wherein:

[0015] Het is an oxadiazolyl group;

[0016] R¹ is a hydrogen atom, a lower alkyl group, a cyclo-lower alkylgroup, a trifluoromethyl group, a lower alkenyl group, a lower alkynylgroup, a lower alkoxy group, a lower alkoxy-lower alkyl group, ahydroxy-lower alkyl group, a substituted or unsubstituted aryl group, ora substituted or unsubstituted heteroaryl group; and

[0017] R² is a hydrogen atom, a lower alkyl group, a cyclo-lower alkylgroup, a cyclo-lower alkylmethyl group, a lower alkenyl group, acyclo-lower alkenyl group, a lower alkynyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted heteroarylgroup, or a physiologically acceptable acid addition salt thereof.

[0018] Another object of the present invention is to provide use of a5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)- one derivative ofthe formula (I) or a physiologically acceptable acid addition saltthereof for the manufacture of a medicine for the prevention andtreatment of neurodegenerative diseases.

[0019] A further object of the present invention is to provide a methodfor the prevention and/or treatment of neurodegenerative diseases inmammals (including human beings), which comprises administering aneffective amount of a5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of theformula (I) or a physiologically acceptable acid addition salt thereofto said mammals in need of such prevention and/or treatment.

BEST MODE FOR CARRYING OUT THE INVENTION

[0020] The present inventors have found that the5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivative of theabove formula (I) can be used for the prevention and/or treatment ofneurodegenerative diseases with hypofunction of glutamic acid receptor,such as Alzheimer's disease or schizophrenia, in mammals (includinghuman beings).

[0021] The compounds used for the prevention and treatment ofneurodegenerative diseases of the present invention are shown by theformula (I), and the preferred compounds are those of the formula (I)wherein R¹ is a C₁-C₃ alkyl group, a C₃-C₄ cycloalkyl group, or a C₂-C₃alkenyl group; and R² is a hydrogen atom, a C₁-C₄ alkyl group, a C₃-C₆cycloalkyl group, a substituted or unsubstituted aryl group, or asubstituted or unsubstituted heteroaryl group.

[0022] More preferred compounds are those of the formula (I) wherein R¹is a C₁-C₃ alkyl group or a C₃-C₄ cycloalkyl; and R² is a hydrogen atom,a C₁-C₃ alkyl group, a C₃-C₄ cycloalkyl group, a substituted orunsubstituted phenyl group, or a substituted or unsubstituted heteroarylgroup.

[0023] Further more preferred compounds are the following compounds;

[0024]3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-methylcyclo-propyl)-1,6-naphthyridin-2(1H)-one,

[0025]3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0026]3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0027]3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0028]3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-thienyl)-1,6-naphthyridin-2(1H)-one,

[0029]3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,

[0030]3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-methyl-1,6-naphthyridin-2(1H)-one,

[0031]3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(3-fluorophenyl)-1,6-naphthyridin-2(1H)-one,

[0032]3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0033]3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0034]3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0035]3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,and

[0036]3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3-thienyl)-1,6-naphthyridin-2(1H)-one.

[0037] Suitable examples of physiologically acceptable acid additionsalts of the compounds of the formula (I) are inorganic acid salts suchas hydrochloride, hydrobromide, hydroiodide, sulfate, or phosphate, andorganic acid salts such as oxalate, maleate, fumarate, malonate,lactate, malate, citrate, tartrate, benzoate, methanesulfonate, ortosylate.

[0038] The “lower alkyl group” and “lower alkyl” moiety in the presentdescription denote a straight chain or branched chain alkyl group having1-6 carbon atoms, such as methyl group, ethyl group, propyl group,isopropyl group, butyl group, isobutyl group, tert-butyl group, pentylgroup, and hexyl group.

[0039] The “cyclo-lower alkyl group” denotes a cycloalkyl group having3-6 carbon atoms, such as cyclopropyl group, cyclobutyl group,cyclopentyl group, and cyclohexyl group, and these rings may beoptionally substituted by a C₁-C₃ alkyl group or a halogen atom.

[0040] The “lower alkenyl group” and “lower alkynyl group” have astraight or branched carbon chain having 2-6 carbon atoms, and include,for example, allyl group, 1-propenyl group, propargyl group, and2-methyl-1-ethynyl group.

[0041] The “cyclo-lower alkenyl group” denotes a cycloalkenyl grouphaving 5-6 carbon atoms, such as cyclohexenyl group.

[0042] The “lower alkoxy group” and “lower alkoxy” moiety denote astraight chain or branched chain alkoxy group having 1-6 carbon atoms,such as methoxy group, ethoxy group, propoxy group, isopropyloxy group,butyloxy group, isobutyloxy group, tert-butyloxy group, pentyloxy group,and hexyl group.

[0043] The “aryl group” and “aryl” moiety denote a phenyl group or anaphthyl group, and said ring may optionally have 1-3 substituentsselected from a halogen atom, a C₁-C₃ alkyl group, a trifluoromethylgroup, a hydroxy group, a C₁-C₃ alkoxy group, a trifluoromethoxy group,a cyano group, an amino group, and a nitro group.

[0044] The “heteroaryl group” denotes a 5- to 6-membered aromaticheterocyclic group containing 1-2 hetero atoms, which are, the same ordifferent, selected from nitrogen atom, oxygen atom or sulfur atom, andincludes, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl,pyridyl, pyridazinyl, and pyrimidinyl, wherein such heterocyclic groupmay optionally have 1 to 3 substituents selected from a halogen atom, aC₁-C₃ alkyl group, a hydroxy group, a C₁-C₃ alkoxy group, and an aminogroup.

[0045] Further, the “halogen atom” denotes fluorine atom, chlorine atom,bromine atom or iodine atom.

[0046] The compounds of the formula (I) can be prepared by the methoddisclosed in WO99/03857.

Pharmacological Experiments

[0047] The utility of the compounds of the formula (I) as the medicinefor prevention and treatment of neurodegenerative diseases will beillustrated by the following pharmacological tests using a model forMK-801-induced neuronopathy and the results thereof as to the typicalcompounds of the formula (I).

[0048]3-(5-Methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H)-one(hereinafter, referred to as “Compound A”) was used as a test compound.Compound A can be prepared according to the method disclosed in PCTPublication WO 99/03857.

[0049] Further, MK-801 (dizocilpine maleate) is described in, forexample, Merck Index, 12th Edition, 3451 (1996), and is commerciallyavailable, (for example, (+)MK-801, manufactured by Research BiochemicalInternational)

[0050] Experiment 1

[0051] Inhibitory Effect on MK-801-Induced Neurodegeneration

[0052] The pharmacological test was carried out according to the methodof D. F. Wozniak, et al. [Brain Research, Vol. 707, pp 165-178 (1996)].

[0053] MK-801 was dissolved in physiological saline (concentration 0.1mg/ml) and was subcutaneously (s.c.) administered to three mice (Std-ddYmale mice: 39.9-45.8 g of body weight) in a volume of 0.1 ml per 10 g ofbody weight, i.e., 1 mg/kg. Compound A was suspended in a 0.5%tragacanth solution in a concentration of 0.1 mg/ml, and the resultantsuspension was orally (p.o.) administered to the mice in a volume of 0.1ml per 10 g of body weight, i.e., 1 mg/kg, 30 minutes before MK-801administration. Five hours after MK-801 administration, mice wereperfused with physiological saline and fixed with 10% neutral formalinbuffer solution under etherization. The cerebrum was cut transverselyfrom the anterior termination at approximately 4 mm to the posteriortermination, and then embedded in cold polymerized resin (Technovit7100,manufactured by Kulzer in Germany). The slices containing the PC/RScortex were obtained at four Anterior-Posterior levels at intervals of300 μm from the exposed section of the block, and at each level twoslices (3 μm in thickness) were consecutively obtained. The histologicalchange (on Hematoxylin and eosin stain specimen) and the number ofvacuolized neurons (on Nissl stain specimen) were observed by a lightmicroscope for each 4 slices, respectively. The results are shown inTable 1.

[0054] Table 1 shows the number of vacuolized neurons in the PC/RScortex in the non-treated control group, the group treated with MK-801alone, and the group treated with Compound A before MK-801.

[0055] As shown in Table 1, in the group treated with MK-801 (1 mg/kg)for 5 hours, the vacuolization was remarkably observed in the neurons oflayers III-IV, and the mean number of the vacuolized neurons per mouseremarkably increased from 0 (in non-treated control group) to 30.8 perslice. On the contrary, in the group treated with Compound A (1 mg/kg)prior to MK-801, the number remarkably decreased to 4.3, and in some ofthem no vacuolization was observed. TABLE 1 Vacuolization Animal SliceNo. Mean(/slice) Test Group No. 1 2 3 4 Individual Group Non-treatment01M01 0 0 0 0 0.0 0.0 control group 01M02 0 0 0 0 0.0 01M03 0 0 0 0 0.0MK-801 02M01 41 50 34 19 36.0 30.8 1 mg/kg s.c. 02M02 23 39 42 40 36.0 5h group 02M03 26 24 14 17 20.3 Compound A 03M01 0 0 0 0 0.0 4.3 1 mg/kgp.o. + 03M02 20 12 10 5 11.8 MK-801 03M03 0 0 2 2 1.0 1 mg/kg s.c. 5 hgroup

[0056] As is clear from the above results, Compound A exhibited a potentretardation or inhibition of neurodegeneration in the PC/RS cortexinduced by MK-801.

[0057] Accordingly, the compounds (I) of the present invention areuseful for the treatment of Alzheimer's disease or schizophrenia, as amedicine for the prevention and treatment of neurodegenerative diseaseson the basis of inhibitory effect on neurodegeneration, through thedifferent mechanism from that of the current medicines for theimprovement in neural hypofunction via the activation of cholinergicfunction.

[0058] Usage of Compounds of the Invention as Medicine

[0059] The compounds of the formula (I) can be used as a medicine forthe prevention and treatment of neurodegenerative diseases. They can beadministered through any of oral, parenteral and intrarectal routes,preferably oral route. The dosage thereof may vary depending on theadministration route, kinds of diseases to be treated, symptom/age ofpatients, deal mode (prevention or treatment), etc., but it is usuallyin 0.01 to 10 mg/kg/day, preferably 0.02 to 5 mg/kg/day, which may beadministered at one time or dividedly in several times.

[0060] The compounds of the formula (I) can be used as a medicine forthe prevention and treatment of neurodegenerative diseases alone or inthe form of a pharmaceutical composition, which is generally prepared bymixing with a pharmaceutically acceptable carrier. The pharmaceuticalcomposition may be in the dosage forms such as tablets, capsules,granules, powders, syrups, suspensions, suppositories, gels, sustainedrelease preparations, and injection preparations. These pharmaceuticalcompositions can be prepared by a conventional method. Thepharmaceutically acceptable carrier may be any conventional ones, whichare commonly used in the pharmaceutical field and do not react with thecompounds of the present invention. Suitable examples are lactose,glucose, mannitol, dextrin, starch, corn starch, sucrose,polysaccharide, magnesium aluminometasilicate, synthetic aluminumsilicate, crystalline cellulose, sodium carboxymethylcellulose, calciumcarboxymethylcellulose, hydroxypropyl starch, ion exchange resins,methylcellulose, gelatin, acacia, hydroxypropylcellulose,low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose,poly-vinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid,magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitanfatty acid ester, sodium lauryl sulfate, glycerin, glycerin fatty acidester, purified lanolin, glycerogelatin, polysorbate, macrogol,vegetable oil, wax, liquid paraffin, white petrolatum, nonionicsurfactant, propylene glycol, and water.

[0061] Liquid preparations may be in the form, which is dissolved orsuspended in water or other appropriate medium when used. Further,tablets and granules may be coated in a conventional manner. In the caseof suppositories, the base for them includes cacao butter, glycerinsaturated fatty acid ester, glycerogelatin, macrogol, etc., and in thepreparations, a surfactant or a preservative may optionally be added.Injection preparations may be prepared by dissolving a physiologicallyacceptable acid addition salt of the compound of the formula (I) indistilled water for injection or physiological saline, and thereto maybe optionally added a solubilizer, an isotonic agent, a pH adjustingagent, a buffering agent, a pain-reducing agent or a preservative.

[0062] These pharmaceutical compositions may usually contain thecompound of the formula (I) as an active ingredient in an amount of atleast 0.01% by weight, preferably 0.05-70% by weight. Thesepharmaceutical compositions may optionally contain other therapeuticallyeffective compounds.

[0063] Preparation

[0064] The pharmaceutical compositions of the medicine for theprevention and treatment of neurodegenerative diseases according to thepresent invention are illustrated by the following preparations.Preparation 1: Capsules: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 57 gLactose 10 g Crystalline cellulose 25 g Hydroxypropylcellulose 2 g Lightanhydrous silicic acid 0.5 g Magnesium stearate 0.5 g

[0065] Amongst the above components, the active ingredient, corn starch,lactose and crystalline cellulose are blended, and thereto is addedhydroxypropylcellulose being dissolved in water, and the mixture iskneaded, dried and granulated. To these granules are added magnesiumstearate and light anhydrous silicic acid and mixed. These are filled in1000 capsules to prepare the capsule preparations weighing 100 mg each.Preparation 2: Tablets: 3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 20 gLactose 19 g Crystalline cellulose 10 g Hydroxypropylcellulose 5 gLow-substituted hydroxypropylcellulose 10 g Magnesium stearate 0.5 gLight anhydrous silicic acid 0.5 g

[0066] Amongst the above components, the active ingredient, corn starch,lactose, low-substituted hydroxypropyl-cellulose and crystallinecellulose are blended, and thereto is added hydroxypropylcellulose beingdissolved in water, and the mixture is kneaded, dried and granulated.Thereto are added magnesium stearate and light anhydrous silicic acid,and the mixture is compressed to give tablet cores having the activeingredient weighing 5 mg content (alternatively indicated as the weightof 70 mg each tablet) . Then, said tablet cores are coated to formfilm-coated tablets by a conventional method, usinghydroxypropylmethylcellulose, macrogol, titanium oxide, talc and lightanhydrous silicic acid. Preparation 3: 1 % Powders:3-(5-Methyl-1,2,4-oxadiazol-3-yl)- 5 g5-(3-methoxyphenyl)-1,6-naphthyridin- 2 (1H)-one Corn starch 150 gLactose 250 g Hydroxypropylcellulose 20 g Light anhydrous silicic acid75 g

[0067] In a conventional manner, above components are blended,granulated and regulated using a high-shear granulator, and then theretois added light anhydrous silicic acid to give 1% powders.

[0068] Industrial Applicability

[0069] As explained above, the compounds of the formula (I) showremarked potent retardation or inhibition of neurodegeneration due tothe hypofunction of glutamic acid receptor and also exhibit lowtoxicity, and hence, it can be used for the prevention and/or treatmentof neurodegenerative diseases such as Alzheimer's disease orschizophrenia in mammals (including human beings) as a medicine for theprevention and treatment of neurodegenerative diseases.

1. A medicine for prevention and treatment of neurodegenerative diseasescomprising a 5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-onederivative of the following formula (I):

wherein: Het is an oxadiazolyl group; R¹ is a hydrogen atom, a loweralkyl group, a cyclo-lower alkyl group, a trifluoromethyl group, a loweralkenyl group, a lower alkynyl group, a lower alkoxy group, a loweralkoxy-lower alkyl group, a hydroxy-lower alkyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted heteroarylgroup; and R² is a hydrogen atom, a lower alkyl group, a cyclo-loweralkyl group, a cyclo-lower alkylmethyl group, a lower alkenyl group, acyclo-lower alkenyl group, a lower alkynyl group, a substituted orunsubstituted aryl group, or a substituted or unsubstituted heteroarylgroup, or a physiologically acceptable acid addition salt thereof. 2.The medicine for prevention and treatment of neurodegenerative diseasesaccording to claim 1, wherein R¹ is a C₁ to C₃ alkyl group, a C₃ to C₄cycloalkyl group, or a C₂ to C₃ alkenyl group, and R² is a hydrogenatom, a C₁ to C₄ alkyl group, a C₃ to C₆ cycloalkyl group, a substitutedor unsubstituted aryl group, or a substituted or unsubstitutedheteroaryl group.
 3. The medicine for prevention and treatment ofneurodegenerative diseases according to claim 2, wherein R¹ is a C₁ toC₃ alkyl group or C₃ to C₄ cycloalkyl group, and R² is a hydrogen atom,a C₁ to C₃ alkyl group, a C₃ to C₄ cycloalkyl group, a substituted orunsubstituted phenyl group, or a substituted or unsubstituted heteroarylgroup.
 4. A medicine for prevention and treatment of neurodegenerativediseases comprising a5-substituted-3-oxadiazolyl-1,6-naphthyridin-2(1H)-one derivativeselected from3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-methylcyclo-propyl)-1,6-naphthyridin-2(1H)-one,3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-methoxyphenyl)-1,6-naphthyridine-2(1H)-one,3-(5-ethyl-1,2,4-oxadiazol-3-yl)-5-(2-thienyl)-1,6-naphthyridin-2(1H)-one,3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-methyl-1,6-naphthyridin-2(1H)-one,3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(3-fluorophenyl)-1,6-naphthyridin-2(1H)-one,3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methylphenyl)-1,6-naphthyridin-2(1H)-one,3-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,3-(3-ethyl-1,2,4-oxadiazol-5-yl)-5-(4-pyridyl)-1,6-naphthyridin-2(1H)-one,and3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-5-(3-thienyl)-1,6-naphthyridin-2(1H)-one,or a physiologically acceptable acid addition salt thereof.
 5. Amedicine for prevention and treatment of neurodegenerative diseasescomprising3-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(3-methoxyphenyl)-1,6-naphthyridin-2(1H)-oneor a physiologically acceptable acid addition salt thereof.
 6. Use ofthe compound according to any one of claims 1 to 4 for the manufactureof a medicine for prevention and treatment of neurodegenerativediseases.
 7. Use of the compound according to claim 5 for themanufacture of a medicine for prevention and treatment ofneurodegenerative diseases.
 8. Use of the compound according to any oneof claims 1 to 5, wherein the neurodegenerative disease is Alzheimer'sdisease or schizophrenia.
 9. A method for prevention and/or treatment ofneurodegenerative diseases of a mammal which comprises administering aneffective amount of the compound according to any one of claims 1 to 4,to said mammal in need of such prevention and/or treatment ofneurodegenerative diseases.
 10. A method for prevention and/or treatmentof neurodegenerative diseases of a mammal which comprises administeringan effective amount of the compound according to claim 5, to said mammalin need of such prevention and/or treatment of neurodegenerativediseases.
 11. The method for prevention and/or treatment according toclaim 9 or 10, wherein the neurodegenerative disease is Alzheimer'sdisease or schizophrenia.
 12. The method for prevention and/or treatmentaccording to any one of claims 9 to 11, wherein the mammal is human.